Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1-3 Infections.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Non-invasive assessment of fibrosis regression and portal hypertension in patients with advanced chronic hepatitis C virus (HCV)-associated liver disease and sustained virologic response (SVR): 3 years follow-up of a prospective longitudinal study.

Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1-75) kPa] and EOT [21.3(6.7-73.5) kPa; p < .0001] and EOT and FU144 [16(4.1-75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2-4.1) m/s] and FU144 [1.7(0.9-4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.

Efficacy of Direct-acting Antivirals for Chronic Hepatitis C Virus Infection in People Who Inject Drugs or Receive Opioid Substitution Therapy: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment uptake for hepatitis C virus (HCV) infection in people who inject drugs (PWID) and patients on opioid substitution therapy (OST) is still low despite treatment guidelines that advocate the use of direct-acting antivirals (DAAs) in all patients. Our aim in this review was to investigate treatment outcomes among PWID and patients on OST in comparison to control cohorts. METHODS: A search of Embase, Medline, PubMed, and Web of Science (from October 2010 to March 2018) was conducted to assess sustained virologic response (SVR), discontinuation rates, adherence, and HCV reinfection in PWID and patients on OST. RESULTS: We identified 11 primary articles and 12 conference abstracts comprising 1702 patients on OST, 538 PWID, and 19 723 patients who served as controls. Among patients on OST, the pooled SVR was 90% (95% confidence interval [CI], 87% to 93%) and pooled treatment discontinuation rate was 7% (95% CI, 4% to 11%). Similarly, the pooled SVR was 88% (95% CI, 80% to 93%) in PWID and the pooled treatment discontinuation rate was 9% (95% CI, 5% to 15%). There was no significant difference regarding pooled rates of SVR, adherence, and discontinuation between patients on OST and controls as well as between PWID and controls. HCV reinfection rates among patients on OST ranged from 0.0 to 12.5 per 100 person-years. CONCLUSIONS: HCV treatment outcomes in PWID and patients on OST are similar to those in patients without a history of injecting drugs, supporting current guideline recommendations to treat HCV in these patient populations.

Quinolone and Multidrug Resistance Predicts Failure of Antibiotic Prophylaxis of Spontaneous Bacterial Peritonitis.

BACKGROUND: The efficacy of antibiotic prophylaxis to prevent spontaneous bacterial peritonitis (SBP) in patients colonized with multidrug-resistant organisms (MDROs) is unknown. We evaluated the effectiveness of fluoroquinolone-based SBP prophylaxis in an era and area of frequent antibiotic resistance. METHODS: This is a prospective observational study in patients with liver cirrhosis and an indication for fluoroquinolone-based prophylaxis of SBP. Patients were recruited and followed in a large German tertiary reference center with comprehensive microbiological and clinical monitoring performed at baseline and after 30, 60, 90, and 180 days of prophylaxis. RESULTS: Overall, 77 patients received antibiotic prophylaxis for an average of 93 days. Baseline prevalence of colonization with MDROs was high (N = 39, 50.6%). At least one de novo MDRO was detected in 27 patients (35.1%) during antibiotic prophylaxis; 33 patients (42.9%) developed secondary infections, including 14 cases (17.9%) of infections with MDROs, and 13 cases (16.9%) of de novo/recurrent SBP. Thirty patients (39.0%) died during follow-up. Significantly higher risks of SBP development during antibiotic prophylaxis were observed for patients with versus without any apparent MDROs (P = .009), vancomycin-resistant enterococci (P = .008), multidrug-resistant gram-negative bacteria (P = .016), or quinolone-resistant gram-negative bacteria (QR-GNB) (P = .015). In competing risk analysis, QR-GNB were independently associated with prophylaxis failure (hazard ratio, 3.39; P = .045) and infections with QR-GNB were independently associated with death before SBP (subdistribution hazard risk, 6.47; P = .034). CONCLUSIONS: Antibiotic prophylaxis of SBP appears to be less efficient in patients with known MDROs. Regular MDRO screening seems to be useful to tailor treatment of secondary infections and re-evaluate antibiotic prophylaxis in case of selection of quinolone resistance.

Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen.

OBJECTIVES: To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. METHODS: Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. RESULTS: We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. CONCLUSIONS: One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

Resistance-associated substitutions in patients with chronic hepatitis C virus genotype 4 infection.

Data on the prevalence of resistance-associated substitutions (RASs) and their implications for treatment with direct-acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4-infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA-naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P < .0001). RASsL28V, L30R and M31L pre-existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein-protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance-tailored retreatment using first- and second-generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first-line treatment regimens.

Treatment outcomes in hepatitis C virus genotype 1a infected patients with and without baseline NS5A resistance-associated substitutions.

BACKGROUND&AIMS: The presence of baseline resistance-associated substitutions (RASs) reduced sustained virologic response (SVR) rates in chronic hepatitis C virus (HCV) genotype 1a infected patients treated with Elbasvir/Grazoprevir (EBR/GZR). This study aimed to evaluate the frequency of NS5A RASs and treatment outcomes in patients for whom EBR/GZR was intended. METHODS: We sequenced NS5A in 832 samples from German genotype1a-infected DAA-naïve patients population-based, which were collected in the European Resistance Database. Treatment outcomes and clinical parameters were evaluated in 519 of these patients retrospectively. RESULTS: Overall, 6.5% of patients harbored EBR-specific NS5A RASs at baseline, including Q30H/R (3.3%), L31M (1.8%), Y93H (1.6%) and other individual variants. Antiviral treatment, including EBR/GZR, was initiated in 88% of patients. In the absence of RASs, the majority of patients received EBR/GZR for 12 weeks (57%) and the SVR rate was 97% compared to 99% SVR achieved using other DAA regimens (LDV/SOF±RBV, G/P, PrOD+RBV, VEL/SOF). Various regimens were used in the presence of RASs and SVR rates were high following treatment with LDV/SOF (100%), G/P (83%), PrOD/RBV (100%), VEL/SOF (100%), SMV/SOF (100%) and EBR/GZR+RBV for 16 weeks (100%). However, two patients received EBR/GZR for 16 weeks without RBV and one relapsed. CONCLUSIONS: EBR/GZR treatment with or without RBV for 12 or 16 weeks according to a baseline RAS analysis was highly effective with ≥97% SVR in patients with genotype 1a. EBR/GZR without RBV should be avoided in patients with RASs. High SVR rates were also achieved using other 8 or 12 weeks DAA regimens.

Capnography monitoring of non-anesthesiologist provided sedation during percutaneous endoscopic gastrostomy placement: A prospective, controlled, randomized trial.

BACKGROUND AND AIM: A number of studies were able to show a reduction of hypoxemia episodes during procedural sedation through the use of capnography (CA). The present study investigates the number of episodes of hypoxemia during percutaneous endoscopic gastrostomy (PEG) placement with propofol sedation comparing standard monitoring (SM) versus SM with additional CA surveillance. METHODS: In this single center randomized controlled trial, 150 patients were prospectively randomized 1:1 in either the SM group or the CA group after stratification for ASA class, PEG method (push or pull method), presence of head and neck tumor, and tracheostomy. CA analysis was performed for all patients but was blinded for the endoscopic team in the SM group. RESULTS: In the SM group, 57% episodes of hypoxemia (SpO2  < 90% for > 15 s) and 41% episodes of severe hypoxemia (SpO2  < 85% for > 15 s) were observed in comparison with 28% and 20% in the CA group, respectively. Odds ratios for hypoxemia and severe hypoxemia were 0.29 (confidence interval 0.15-0.57; P = 0.0005) and 0.35 (confidence interval 0.17-0.73; P = 0.008) in favor of the CA group. On average, CA was able to detect imminent mild and severe hypoxemia 83 and 99 s before standard monitoring. Standard monitoring represented an independent risk factor for hypoxemia and severe hypoxemia. CONCLUSIONS: Respiratory complications of sedation during PEG placement are frequent events. CA is able to detect imminent hypoxemia at an early time point. This allows an early intervention and consecutively the avoidance of mild and severe hypoxemia. Therefore, CA monitoring can be recommended particularly during PEG insertion procedures.

Sofosbuvir, velpatasvir, and voxilaprevir for patients with failure of previous direct-acting antiviral therapy for chronic hepatitis C: Results from the German Hepatitis C-Registry (DHC-R).

Despite the high effectiveness of direct-acting antivirals for the treatment of hepatitis C, a small proportion of patients do not respond to approved regimens. The combination regimen of SOF/VEL/VOX was recently approved for patients with failure to prior NS5A-based treatment. In this German real-world cohort including patients with cirrhosis (27.3 %) and previous decompensation events, 12 weeks of SOF/VEL/VOX resulted in high virologic response rates irrespective of disease severity and prior DAA regimen. Adverse events were mostly mild or moderate and comparable to those seen in the approval studies.

Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy - data from the German hepatitis C registry (DHC-R).

BACKGROUND: Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. PATIENTS AND METHODS: Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. RESULTS: Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). CONCLUSIONS: Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective.

Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals.

BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Performance of Three Common Hepatitis C Virus (HCV) Genotyping Assays for Identification of HCV Genotype 2/1 Chimeras.

Besides seven major hepatitis C virus (HCV) genotypes (GT), a number of intergenotypic recombinant strains have been described. These so-called chimeras combine genetic characteristics of different HCV genotypes. However, correct genotype classification is important, as choice and duration of direct-acting antiviral (DAA) treatment is mainly based on the viral genotype. Therefore, misclassification of chimeras might lead to suboptimal treatment of patients infected with these strains. For example, 2k/1b chimeras are typically described as HCV genotype 2 strains by commercially available hybridization assays, but real-time PCR-based tests recognizing another HCV region might be more suitable for correct chimera detection. In this study, the analytic capacity of the hybridization-assay Versant HCV Genotype 2.0 (LiPA 2.0) and the real-time PCR-based-assays cobas HCV GT and Abbott RealTime HCV Genotype II were tested in a selected cohort of 230 patients infected with HCV genotype 1 (n = 53) and 2 (n = 177) and 48 patients infected with HCV 2/1 chimeric strains. While the Versant HCV Genotype 2.0 (LiPA 2.0) assay failed to identify chimeras in all of the patients (48/48, 100%), cobas HCV GT and Abbott HCV Genotype II assays identified chimeras correctly in 90% (43/48) and 65% (31/48) of the cases, respectively. In conclusion, while the hybridization-based Versant HCV Genotype 2.0 (LiPA 2.0) assay seems to be unsuitable for detection of HCV 2/1 chimeras, use of the real-time PCR-based assays cobas HCV GT and Abbott RealTime HCV Genotype II led to a higher rate of chimera detection.

Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: A systematic review and meta-analysis.

BACKGROUND&AIMS: Since the introduction of direct-acting antivirals (DAAs) several studies have reported high efficacy and safety in Hepatitis C infected patients, even in those earlier considered difficult-to-treat. We aimed to assess the efficacy and safety of DAA therapy in elderly patients. METHODS: The PubMed MEDLINE, Embase and Cochrane databases were searched through July 2018. Two independent researchers extracted data and assessed the quality and risk of bias. Risk ratios (RRs) were pooled using random effects models. The primary outcome was efficacy of DAA therapy assessed by the RR for non-sustained virologic response (SVR) among patients aged <65 vs ≥65 years. RESULTS: Overall, we identified 63 studies including 34 082 patients treated with different DAAs. Risk for non-SVR was comparable in patients <65 and ≥65 years of age (RR 1.00, 95% CI 0.86-1.15; P = 0.979) and even lower in a subgroup analysis of cirrhotic patients ≥65 years of age (RR 0.59, 95% CI 0.35-0.99, P = 0.044). Risk for non-SVR was similar between age groups in all other subgroup analyses. Elderly patients had a significantly increased risk of adverse events (AEs) (RR 1.30, 95% CI 1.11-1.52, P = 0.001), but not for serious adverse events (P = 0.43) or treatment discontinuation (P = 0.15). Risk for anaemia if treated with additional ribavirin was 2.84 (95% CI 1.73-4.66, P < 0.001) in elderly patients compared to patients <65 years. CONCLUSION: Our results show that DAAs are highly effective and safe in elderly patients. Ribavirin should be avoided in the elderly as more AEs and particularly anaemia is observed. Further cost-effectiveness analyses are needed to evaluate the socio-economic benefit of treating elderly people without advanced liver disease.

Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response.

BACKGROUND & AIMS: Curing hepatitis C virus (HCV) infection reduces the risk of hepatocellular carcinoma (HCC) development, yet HCC occurs despite sustained virologic response (SVR) in 2%-8% of cirrhotic patients. Sphingolipids (SLs) have been identified as new biomarkers of chronic liver disease and HCC. The aim of this study was to evaluate serum SLs as diagnostic HCC biomarkers in patients with HCV-associated cirrhosis at SVR12. METHODS: From 2014 to 2016, 166 patients with HCV-cirrhosis and SVR were recruited and SL profiles were measured at baseline and 12 weeks after completion of direct-acting antiviral (DAA) therapy. All patients received HCC surveillance in line with current guideline recommendations. Minimum follow-up period comprised 6 months. RESULTS: Our study included 130 (78%) patients without history of HCC, 25 (15%) with history of HCC prior DAA therapy and 11 (7%) patients with de novo HCC after FU12. In those with upcoming de novo HCC serum C24DHC (P = 0.006), C24:1DHC (P = 0.048) and C16Cer (P = 0.011) were significantly upregulated at FU12, but not AFP (P = 0.138). Contemporaneous ultrasound did not visualize HCC, at this time. C16Cer stayed sole independent predictor with high diagnostic accuracy of AFP-positive (AUC = 0.741) and -negative (AUC = 0.766) HCC development. Serum SL parameters decreased from baseline to SVR12. CONCLUSIONS: C24DHC, C24:1DHC and especially C16Cer were superior to AFP in early detection of AFP-positive and -negative de novo HCC development. We observed significant SL profile changes upon SVR. SLs may play a role in non-invasive HCC surveillance and hepatocarcinogenesis.

Prophylactic percutaneous endoscopic gastrostomy in patients with head and neck cancer: Influence on nutritional status, utilisation rate and complications.

BACKGROUND: Patients with head and neck cancer (HNC) are at high risk for malnutrition because of tumour localisation and therapy. Prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement is common practice to prevent malnutrition. OBJECTIVE: To investigate the benefits of prophylactic PEG tube placement for HNC patients in terms of the influence on patients' nutritional status, utilisation rate, complications and to identify the predictors of PEG tube utilisation. METHODS: All consecutive HNC patients who underwent prophylactic PEG tube insertion between 1 January 2011 and 31 December 2012 prior to therapy were enrolled. The PEG tube utilisation rate, complications, the patients' nutritional status and tumour therapy were evaluated with the help of electronic patient charts and telephone interviews. RESULTS: A total of 181 patients (48 female, median 67.5 years) were included. The PEG utilisation rate in the entire cohort was 91.7%. One hundred and forty-nine patients (82.3%) used the PEG tube for total enteral nutrition, 17 patients (9.4%) for supplemental nutrition and 15 patients (8.3%) made no use of the PEG tube. Peristomal wound infections were the most common complications (40.3%) in this study. A high Nutritional Risk Screening (NRS) score prior to tube insertion was found to be independently associated with PEG utilisation. No significant weight changes were observed across the three patient subgroups. CONCLUSIONS: The overall PEG tube utilisation rate was high in this study. However, given the high rate of infections, diligent patient selection is crucial in order to determine which patients benefit most from prophylactic PEG tube insertion.

Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients.

Background: Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal. Methods: We analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells. Results: We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients. Conclusion: Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.

Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection.

Treatment of chronic hepatitis C virus infection has been revolutionised by the development of direct-acting antivirals (DAAs). All-oral, once-daily, 8- to 12-week treatment regimens are now standard of care, with viral eradication possible in >95% of patients across different populations. Despite these advances, several unresolved issues remain, including treatment of patients with hepatitis C virus genotype 3, chronic kidney disease, and those in whom DAA therapy has previously failed. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Herein, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C.

BACKGROUND & AIMS: Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8-week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. METHODS: The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. RESULTS: Overall, 84.6% (2,034/2,404) of the safety population (intention-to-treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). CONCLUSIONS: Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. LAY SUMMARY: In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12-week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS).

Clinical significance of detectable and quantifiable HCV RNA at the end of treatment with ledipasvir/sofosbuvir in GT1 patients.

BACKGROUND & AIMS: AASLD/IDSA treatment guidelines for hepatitis C virus (HCV) infection state that testing for quantitative HCV RNA can be considered at the end of antiviral treatment (EOT) with interferon-free regimens. However, it remains unclear how to respond to a detectable or even quantifiable HCV RNA result. The aim of this study was to analyse the frequency and predictive value of detectable and quantifiable HCV RNA results at the EOT in patients with HCV genotype 1 infection treated with ledipasvir (LDV) and sofosbuvir (SOF) ± ribavirin (RBV) in a large real-world cohort. METHODS: A retrospective analysis of the DHC-R (Deutsches Hepatitis C-Register, German Hepatitis C-Registry) cohort was performed including all patients who were treated with LDV/SOF ± RBV and in whom HCV RNA testing was done with either the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) or the Abbott RealTime HCV assay (ART). RESULTS: The frequency of detectable HCV RNA at the EOT was 7% in this real-world study involving 471 patients. Furthermore, 3% of the patients (n = 14/471) even had quantifiable viral load at the EOT. Detectable and quantifiable results were more frequent if the ART was used for testing. However, SVR was achieved by 32/33 patients (97%) with detectable and even by all 14 patients (100%) with quantifiable HCV RNA results at the EOT. CONCLUSION: Detectable and even quantifiable HCV RNA results are quite frequent if highly sensitive HCV RNA assays are used. However, treatment prolongation is not indicated, as SVR rates remain high in these patients.